PROJECT SUMMARY/ABSTRACT Poly- and perfluorinated alkyl substances (PFASs) are widely used industrial chemicals, but widespread human PFAS exposures from contaminated sites and bioaccumulation in food-chains were discovered less than 20 years ago, and the full range of adverse health effects is incompletely known. While the U.S. EPA published limits for water contamination in 2009, these limits remain provisional and may be as much as two orders of magnitude too high. Thus, recent evidence suggests that current PFAS exposures may cause adverse effects on the immune system and other sensitive tissues and organs, even at exposures far below provisional exposure limits. Further, recent evidence, including our own studies, suggests that early-life exposure to PFASs may contribute to the development of metabolic diseases, including obesity and type 2 diabetes, which constitute major public health problems. Following our discovery that PFAS exposure is associated with decreased antibody response to certain childhood vaccinations, we hypothesize that PFAS- induced inflammation may be involved in obesogenic effects of PFAS exposure. We also recently discovered that most PFASs are transferred via human milk, thereby resulting in peak exposures at the time of weaning. With the aim to provide improved risk characterization in affected communities, we will determine the possible links between PFAS exposure profiles, immune dysfunction, and metabolic abnormalities by examining an already established birth cohort from the Faroe Islands (N = 490) at age 9 years. We have chosen this epidemiological setting as close to ideal to explore the associations between age-related PFAS exposure profiles and metabolic abnormalities. Relying on an already established birth cohort that has been supported by NIEHS, the Project will be highly efficient and utilize exposure and outcome data covering a 9-year span within the project duration, while taking advantage of clinical information, exposure data, and banked serum samples from birth and clinical examinations at ages 18 months and 5 years. Due to the homogeneity of the Faroese population, the wide range of exposures, and the high participation rate in the clinical follow-up, this epidemiological setting represents advantages that would be nearly impossible to match anywhere else. In addition, comparable cohorts will be included in pooled statistical analyses to increase the statistical power. The data analysis will take into account important covariates, including exposures to other environmental chemicals, and we will explore the influence of child sex and diet on PFAS-associated effects, as well as conduct benchmark dose calculations for possible use in risk characterization in U.S. populations exposed to PFASs. In the selection and evaluation of biomarkers and interpretation of the results, we will be in continuous coordination with Project 3 in regard to the causal role of PFASs on metabolic and immune dysfunction. The present project will also link to Projects 1 and 4 and the CEC and RTC by contributing to the development of new biomarkers for application in prevention efforts to protect exposed populations.